Interventions for spinal muscular atrophy: an impetus for newborn screening

Abstract

At the end of May, 2021 a 5-month-old baby became the first in the UK to receive Zolgensma, a gene replacement therapy for spinal muscular atrophy (SMA). His treatment follows a deal announced in March between the UK’s National Health Service and Novartis that will see the £1 795 million drug sold for an undisclosed discount. Following approvals by regulatory bodies, including the US Food and Drug Administration (FDA), European Medicines Agency and Japanese Ministry of Health, Labour and Welfare, the life-changing therapy is now available in up to 40 countries worldwide. Novartis have reconfirmed their commitment to a global managed access programme that will see the allocation of 100 doses per year free-ofcharge to children who would otherwise not have access to the treatment. SMA is a group of disorders characterised by loss of motor neurons in the spinal cord, resulting in muscle atrophy, weakness, and paralysis. The progressive muscle wasting affects all voluntary muscles, leading to movement and respiratory problems. The severity of disease varies with age of onset. In the most severe form (type 1), symptom onset begins within the first 6 months of life and is associated with a typical life expectancy of less than 2 years. Less severe forms (types 2 and 3) are diagnosed later in childhood, while type 4 typically presents in adulthood. SMA is an autosomal recessive condition caused by mutation in the SMN1 gene, which encodes a protein (SMN) essential for motor neuron survival. 94% of cases have a deletion affecting exon 7 of SMN1. The phenotypic severity of SMA is modified by the presence of copy number alterations in a second gene, SMN2, that also encodes SMN. A single nucleotide difference between the two genes results in approximately 90% of the transcripts from SMN2 producing a truncated, biologically inactive protein. Genetic testing can predict the clinical course of SMA and is important to inform medical care for the patient, which, until recent years, was mainly supportive. Zolgensma was the second therapy to be approved globally for SMA treatment, receiving approval from the US FDA in 2019. It is a gene replacement therapy that delivers a functional copy of SMN1 in an adeno-associated virus 9 vector. In May in JAMA Neurology, the 5-year interim results of the long-term extension of the START trial, reported the safety and clinical durability of onasemnogene abeparvovec (the generic name for Zolgensma). 13 children (median age 38 9 months) with type 1 SMA and 2 copies of SMN2 who had previously been treated with either a low-dose (6 7£ 10 vector genomes [vg]/kg) or therapeutic dose (2 0£ 10 vg/kg) of onasemnogene abeparvovec were observed for adverse events. All ten of the children who received a therapeutic dose were alive, had maintained their previously acquired motor milestones, and did not require any new permanent ventilation support. The three children in the lowdose cohort also remained alive, with one now requiring permanent